Process for the preparation of tablets comprising s-adenosylmethionine

ABSTRACT

There is described a process for the preparation of tablets comprising S-adenosylmethionine which comprises blending S-adenosylmethionine with calcium sulfate and/or phosphate, calcium and/or magnesium carbonate, glycerol behenate and or palmtostearate and silica and compressing the resulting mixture. The tablets obtainable by the process of the invention are stable and show a low relative humidity and hygroscopicity.

[0001] The present invention relates to a process for the preparation oftablets comprising S-adenosylmethionine. Particularly, this inventionrelates to a process for the preparation of stable tablets comprisingS-adenosylmethionine and/or a pharmaceutically and/or dietarilyacceptable derivatives thereof.

[0002] It is well known that S-adenosylmethionine (hereinafter “SAMe” orthe “active ingredient”) is a compound endowed with a poor stability ata temperature higher than 0° C. and, accordingly, the pharmaceuticaland/or dietary compositions comprising it, reflect such poor stability,this having plain negative effects, on their preservation and storage,also for short periods of time.

[0003] U.S. Pat. No. 3,954,726 and U.S. Pat. No. 4,057,686 describesalts of SAMe somewhat stable, at a temperature up to 25° C. and 45° C.,respectively.

[0004] U.S. Pat. No. 4,465,672 also describes stable salts of SAMe,among which the sulfate p-toluensulfonate, with 5 moles of an organicsulfonic acid having a pK lower than 2.5 together with a process for thepreparation of compositions comprising such salts; the process involvesthe preparation of a concentrated aqueous solution of one of thementioned raw salts of SAMe, the purification of this solution and itselution through a diluted aqueous solution of the selected sulfonicacid, the titration of the resulting eluate, its concentration andlyophilization.

[0005] Due to the high unstability of SAMe and the derivatives thereof,an aqueous environment would show the limits of this process which,although initially succeeding in maintaining the residual humidity, isinadequate in maintaining the initial starting stability of the SAMesalts in oral solid formulations, because of the high hygroscopicitythereof.

[0006] U.S. Pat. No. 6,093,703 either, which discloses the usefulness ofpharmaceutical compounds comprising at least one active ingredient,among which SAMe, in the treatment of neurological complications inpatients suffering from AIDS, describes compositions based on SAMe saltssuch as, for example, disulfate p-toluensulfonate which, although havinga residual moisture (K.F.) initially equal to about 2%, result to beunstable in time due to the high hygroscopicity thereof.

[0007] The Applicant observed how SAMe and the derivatives thereof,produced according to the described method, result to be howeverhygroscopic when exposed to the air and therefore unstable in time.

[0008] The packaging of the known compositions, comprising SAMe and thederivatives thereof, results to be particularly toilful and expensivedue to the high hygroscopicity of the active ingredient, this causingthe rapid degradation thereof, unpleasant smells also in the presence ofimpurity traces; accordingly, substantially anhydrous environments areneeded (in fact the tablets are generally packed in aluminium/aluminiumblisters).

[0009] Also the accidental exposure to atmospheric humidity, inevitablyoccuring during the industrial processes (f.i. due to microfractures inthe blisters wherein tablets are generally contained), and consequentlycausing the degradation of SAMe and of the derivatives thereof in theknown oral formulations, due to their high hygroscopicity, makes evidentthe need to develop a process enabling the preparation of compositionsshowing a lower hygroscopicity and therefore a higher stability.

[0010] According to a first aspect, this invention describes a processfor the preparation of tablets comprising SAMe and/or one of thepharmaceutically and/or dietarily acceptable derivatives thereof,comprising at a relative humidity, at 20° C., lower or equal to 20%, thefollowing steps:

[0011] a) blending of the active principle SAMe and/or apharmaceutically and dietarily acceptable derivative thereof with1.0-30.0% of calcium sulfate and/or phosphate, 1.0-10.0% of calciumand/or magnesium carbonate, 1.0-15.0% of glycerol behenate and/orpalmitostearate and 0.5-5.0% of silica, the amounts being expressed asweight percentages to the weight of SAMe;

[0012] b) compression of the mixture resulting from step a);

[0013] c) coating of the mixture resulting from step b) by 0.5-2.5% ofBiogapress® vegetal and 0.5-2.5% of Labrafac® cc, at a temperature of35°-45° C., after 10 to 30 minutes at 60-65° C., the amounts beingexpressed as weight percentages to the total weight of the mixtureresulting from step b).

[0014] SAMe in the present invention means both the racemic mixture[(S,R)—SAMe] and the single diastereoisomers(RS)-(+)—S-adenosyl-L-methionine [(RS)-(+)—SAMe)] and (SS)-(+)—Sadenosyl-L-methionine [(SS)-(+)—SAMe)], also in mixtures different fromthe racemic one.

[0015] According to a preferred embodiment, after the blending step a),the process of the invention comprises:

[0016] a′) the pre-compression of the mixture resulting from step a);and

[0017] a″) the granulation of the mixture resulting from step a′).

[0018] Examples of pharmaceutically and dietarily acceptable SAMederivatives are preferably selected among the salts with the sulfuricacid and/or the p-toluensulfonic acid.

[0019] The process of the invention allows to obtain tablets that,though having the same dosage of the active ingredient, with respect tothe commercialised tablets such as, for example, Samyr®, are poorlyhygroscopic, show a good compressibility, have a low moisture and arestable.

[0020] Preferably, in step a), 1.0-30.0% by weight to the SAMe weight ofanhydrous microcrystalline is added.

[0021] The tablets obtained from step a) are granulated (generally,their dimension being equal to 1200-1600 μm), then compressed, thusobtaining the core of the tablets, which will be then coated by aprotective film comprising Biogapress® vegetal and Labrafac®cc.

[0022] The process of the invention, according to a further embodiment,comprises the coating of the tablets protected with a gastroresistantfilm. In particular, this gastroresistant film comprises 1.0-5.0% ofEudragit®, Shellac® and/or at least a water-soluble salt thereof,1.0-3.0% of titanium dioxide, 1.0-3.0% of talc, 0.1%-1.0% oftriethylcitrate and/or glycerine, 0.004-0.04% of ferric oxide, theamounts being expressed as weight percentages to the total weight of themixture resulting from step b). Shellac® and, in particular, thewater-soluble salts thereof are preferred components; a 1:1 mixture ofpotassium and ammonium salts of Shellac® is particularly preferred.

[0023] According to a further preferred aspect, in step a), at leastanother active ingredient is added, selected among 100-150% ofglucosamine sulfate, 80-120% of chondroitin sulfate, 100-150% ofmethylsulfonylmethane (MSM), 0.1-0.5% of vitamin B₆, 0.04-0.2% ofvitamin B₁₂, 0.03-0.15% of folic acid, the amounts being expressed asweight percentages to the weight of SAMe.

[0024] Any excipient mentioned, i.e. all of the above mentionedcomponents but SAMe, the derivatives thereof and the other abovementioned active ingredients, used in the process of the invention,according to a preferred embodiment, including the gastroresistantcoating, are all-natural ingredients.

[0025] According to a second aspect, the invention describes tabletscomprising SAMe and/or one of the pharmaceutically and/or dietarilyacceptable derivatives thereof obtainable by the above describedprocess.

[0026] The tablets obtainable by the process of the invention comprise,preferably, all-natural components only and undergo an increase inmoisture about four time lower than the tablets containing SAMe (forexample, those sold by Knoll under the trademark Samyr®).

[0027] The following examples illustrate the invention without limitingit.

EXAMPLE 1

[0028] In the following tablets, if not otherwise specified, theinitials used have the meanings and the units of measure listed below:T=temperature (° C.); t=time (months); R.H.=relative humidity (%);AD=adenosine (% by weight to the weight of the SAMe ion);MTAD=methylthioadenosine (% by weight to the weight of the SAMe ion);SAMe=SAMe ion (mg/tablet-tbl); V.B₆=vitamin B6 (mg/tbl); V.B₁₂=vitaminB₁₂ (mg/tbl); AF=folic acid (mg/tbl); SG=glucosamine sulfate (mg/tbl);MSM=methylsolfonylmethane (mg/tbl); SC=chondroitin sulfate (mg/tbl); theproduct SSB® 63 produced by G.T.C. is a mixture 1:1 of the sodium andammonium salts of Shellac®

[0029] 400 mg tablets of SAMe/tbl

[0030] The following table illustrates the composition (amounts inmg/tbl) obtained by the process of the invention. TABLE 1 A. SAMesulfate p-toluensulfonate 830.0 B. Calcium sulfate dihydrate 166.00 C.Calcium carbonate 24.00 D. Silica (Aerosil ®) 10.00 E. Glycerol Behenate(Compritol-e-ato ®) 60.00 F. Anhydrous Microcrystalline cellulose 60.00Core Total weight 1150.00 G. Biogapress ® vegetal (Gattefossè) 7.00 H.Labrafac ® cc (Gattefossè) 7.00 I. Shellac ®(SSB ® 63 produced byG.T.C.) 30.00 L. Titanium dioxide 15.00 M. Talc 15.00 N. Triethylcitrate5.00 O. Iron oxide (Fe₂O₃) 0.10 Tablet Total weight 1229.10

[0031] Core Production:

[0032] 1.1. Blending

[0033] The environment is conditioned at a temperature of 20° C. and ata relative humidity (R.H.) equal to about 20%. Compounds A-F, in theamounts shown in table 1, are put into a 200 l Viani biconical mixer andleft under stirring, blending for about 30 minutes. At the end of thisprocess step, the resulting mixture is transferred into driedrecipients, maintaining humidity and temperature under control.

[0034] 1.2. Pre-Compression

[0035] The pre-compression of the mixture is effected by a Ronchi AMrotative machine equipped with 18 round 25.0 mm punches. The hardness ofthe produced tablets has to be regulated so that a granulate can be thenproduced showing the following rheological characteristics: dust rateequal to about 10% by weight, calculated by granulometry, considering asdust the fraction having particles showing an average dimension lower orequal to 50 μm.

[0036] 1.3 Granulation

[0037] The tablets produced during the first processing step aregranulated on a 1200 μm net always in a controlled humidity environment.

[0038] 1.4 Compression

[0039] The final compression of the granulate is made by a Ronchi AMrotative machine equipped with 18 oblong 19.0×8.8 mm punches setting theweight at 1150 mg/tbl and the compression strength at about 245 N (equalto about 25 kiloponds: kp). The tablets obtained show a hardness equalto about 226-265 N (about 23-27 kp).

[0040] Friability: ≦1.0%; disaggregation time: ≦15 minutes (bothmeasures have been effected according to the method described in theU.S. Pharmacopeia, U.S.P. XXIV ed.); K.F. ≦2.0%; average weightvariation: 1092.5-1207.5 mg.

[0041] Standard processing yield (ratio between the weight of the coresproduced in step 1.4 and the total starting weight of the ingredientsA-F): 97%.

[0042] The following table shows the stability tests carried out, on asingle batch at 40° C. and at 75% R.H. for a period of six months, onthe cores obtained after step 1.4; the table shows the impurities due toSAMe degradation, basically adenosine and methylthioadenosine, expressedas percentage to the weight of SAMe sulfate p-toluensulfonate pertablet. The samples have been preserved into closed and sealed glassbottles, to simulate the final packaging in aluminium/aluminiumblisters. TABLE 2 Batch no 023 stability, 400 mg SAMe/tbl cores Batch(T/t)¹ K.F. AD MTAD SAMe  023 (20/0) 1.87 0.43 1.06 419.01 023A (40/1)1.98 1.11 2.22 414.23 023B (40/3) 1.84 1.99 3.04 402.02 023C (40/6) 1.812.04 3.41 390.89

[0043] The data shown in Table 2 highlight the core stability, showingthe total inertia of the excipients to SAMe.

[0044] 2: Core Protection

[0045] The tablets obtained in the previous processing steps have beencoated in a coater adding a mixture of Biogapress® vegetal (7.0 mg/tbl)and Labrafac® cc (7.0 mg/tbl).

[0046] In a 2.0 l glass container, Biogapress® vegetal and Labrafac® cc.were poured. The mixture was brought to a temperature of about 65° C. bythermostating, obtaining a homogeneous melted mass. After havingpre-treated the coater at 65° C., about 115 kg of tablets were added,heating to 60° C. The melted mass previously prepared was poured on thetablets under stirring to protect the cores. The so treated cores werekept at 60° C. for about 15 minutes, till complete drying up of thecoater basket from the oily layer. Then the in and out air flow wasstopped and, leaving the coater open, the tablets were cooled at 37° C.When the polishing of the cores was good enough (after 10 minutes at 37°C.), about 200 g of talc were poured in the coater, letting the basketrotate for 5 minutes more and, bringing back the cores to 42-44° C., thegastroresistant coating was carried out.

[0047] 3: Core Coating by Gastroresistant Film

[0048] In a container with proper dimension, Shellac® was solubilized at50° C. till a 20% w/v solution was obtained and, under constantstirring, mixed slowly with triethylcitrate.

[0049] In another steel container equipped with stirrer, talc, titaniumdioxide and iron oxide were dispersed in 4.0 l of deionized water. Theresulting suspension was poured into the Shellac® solution washing thecontainer with about 1.0 l of deionized water, then diluting withfurther 4.0 l of deionized water.

[0050] During the first step of the coating, the cores were maintainedat a temperature of 44° C. for about 40 minutes, regularly lowering thenthe temperature, at regular intervals of time, till 42° C. were reachedin the final step.

[0051] After ending the coating of the protected cores, they were letdrying for further 10 minutes at 42° C. Finally, after waiting thelowering of temperature to 36-37° C., the coater was emptied, preservingthe tablets in suitable humidity-proof envelopes.

[0052] Process yield (ratio between the number of tablets put into thecoater and the number of filmed tablets): 99.8% (standard yield).

EXAMPLE 2

[0053] 400 mg SAMe/tbl tablets

[0054] The process described in Example 1 was repeated on an industrialscale using the components and the amounts (in kg) shown in thefollowing table. TABLE 3 A. SAMe sulfate p-toluensulfonate 85.50 B.Calcium Sulfate Dihydrate 17.10 C. Calcium Carbonate 2.47 D. Silica(Aerosil ®) 1.03 E. Glycerol Behenate(Compritol-e-ato ®) 6.18 F.Anhydrous Microcrystalline Cellulose 6.18 G. Biogapress ® vegetal(Gattefossè) 0.70 H. Labrafac ® cc (Gattefossè) 0.70 I. Shellac ® (SSB ®63 of the G.T.C.) 3.00 L. Titanium dioxide 1.50 M. Talc 1.50 N.Triethylcitrate 7.50 O. Iron oxide (Fe₂O₃) 0.01

[0055] The amounts refer to the preparation of a batch of 118.45 kg(103,000 tablets) for the components (A-F) regarding the preparation ofthe core, while for the coating (G-O), the amounts refer to thepreparation of a batch of 115.00 kg (100,000 tablets).

EXAMPLE 3

[0056] 200 mg SAMe/tbl tablets

[0057] Tablets having the composition (amounts in mg/tbl) shown infollowing table have been manufactured according to the processdescribed in Example 1. TABLE 4 A. SAMe sulfate p-toluensulfonate 415.0B. Calcium Sulfate Dihydrate 83.0 C. Calcium Carbonate 12.0 D. Silica(Aerosol) 5.0 E. Glycerol Behenate(Compritol-e-ato ®) 30.0 F. AnhydrousMicrocrystalline Cellulose 30.0 Total core weight 575.0 G. Biogapress ®vegetal (Gattefossè) 3.5 H. Labrafac ® cc (Gattefossè) 3.5 I. Shellac ®(SSB ® 63 of the G.T.C.) 15.0 L. Titanium dioxide 7.5 M. Talc 7.5 N.Triethylcitrate 2.5 O. Iron oxide (Fe₂O₃) 0.1 Tablet Total weight 614.6

[0058] However, in step 1.4, the granulate was compressed by a Ronchi AMrotative machine, equipped with 18 round 11.0 mm punches, adjusting theweight to 575 mg/tbl and the compression strength to about 25 kp. Thetablets obtained showed a hardness between 23 and 27 kp.

[0059] Average weight variation: 546.25-603.75 mg. TABLE 5 Batch no. 015stability, 200 mg SAMe/tbl cores Batch (T/t) K.F. AD MTAD SAMe  015(20/0) 1.77 0.45 1.86 238.11 015A (40/1) 1.88 1.51 4.82 235.56 015B(40/3) 1.99 1.85 5.45 225.23 015C (40/6) 2.05 2.34 5.83 228.13

[0060] The data of Table 5 show the excellent stability of the cores,and confirm the inertia of the selected excipients to SAMe.

[0061] As a proof of the efficacy of the protective coating of the coresaccording the process of the invention, the following table shows theresults concerning the weight increase of two batches of 200 mg SAMe/tblcores, prepared as described in the following example (017-protected byBiogapress® vegetal and Labrafac® cc; batch 018-not protected) left for7 days at 20° C. and to 20% R.H or exposed for the same period of timeat 40° C. and to 75%. R.H. TABLE 6 Batch T/R.H. K.F. 017 20/20 2.10 01740/50 3.31 018 (comparison) 20/20 1.79 018 (comparison) 40/50 6.51

EXAMPLE 4

[0062] 200 mg SAMe/tbl tablets

[0063] The process described in Example 2 was repeated on an industrialscale using the components and amounts (in kg) shown in the followingtable. TABLE 7 A. SAMe sulfate p-toluensulfonate 85.50 B. CalciumSulfate Dihydrate 17.10 C. Calcium Carbonate 2.47 D. Silica (Aerosil ®)1.03 E. Glycerol Behenate(Compritol-e-ato ®) 6.18 F. AnhydrousMicrocrystalline Cellulose 6.18 G. Biogapress ® vegetal (Gattefossè)0.70 H. Labrafac ® cc (Gattefossè) 0.70 I. Shellac ® (SSB ® 63 of theG.T.C.) 3.00 L. Titanium dioxide 1.50 M. Talc 1.50 N. Triethylcitrate0.50 O. Iron oxide (Fe₂O₃) 0.010

[0064] The amounts refer to the preparation of a batch of 118.45 kg(206,000 tablets) for the components (A-F) concerning the preparation ofthe core whereas, as to the coating (G-O), the amounts refer to thepreparation of a batch of 115.00 kg (200,000 tablets).

EXAMPLE 5

[0065] Tablets comprising 600 mg of SAMe/tbl+vitamins B₆/Bl2 and folicacid.

[0066] Tablets having the composition (amounts in mg/tbl) shown in thefollowing table have been manufactured according to the processdescribed in Example 1 TABLE 8 A. SAMe sulfate p-toluensulfonate 1245.0B. Vitamin B₆ 3.0 C. Vitamin B₁₂ 1.0 D. Folic acid 0.8 E. Calciumsulfate dihydrate 249.0 F. Calcium carbonate 36.0 G. Silica (Aerosil ®)15.0 H. Glycerol Behenate (Compritol-e-ato ®) 90.0 I. AnhydrousMicrocrystalline cellulose 90.0 Core total weight 1729.8 G. Biogapress ®vegetal (Gattefossè) 10.5 H. Labrafac ® cc (Gattefossè) 10.5 I.Shellac ® (SSB ® 63 produced by G.T.C.) 43.5 L. Titanium dioxide 22.5 M.Talc 22.5 N. Triethylcitrate 7.5 O. Ferric oxide (Fe₂O₃) 0.1 TabletTotal weight 1846.9

[0067] However, in step 1.4, the granulate was obtained by a Ronchi AMrotative machine, equipped with 18 oblong 23.6×10.8 mm punches,adjusting the weight to 1729.80 mg/tbl and the compression strength toabout 25 kp. The tablets produced had a hardness between 23 and 27 kp.

[0068] Average weight variation: 1643.31-1816.29 mg. TABLE 9 Batch no026 stability, 600 mg SAMe/tbl cores Batch (T/t) K.F. AD MTAD SAMe V. B₆V. B₁₂ AF 026 (20/0) 1.89 0.54 1.12 632.11 3.06 1.05 0.84 026A (40/1)1.75 1.41 3.45 612.23 2.94 1.02 0.85 026B (40/3) 1.97 1.77 4.12 606.892.86 1.03 0.82 026C (40/6) 2.07 2.45 5.36 580.56 2.77 0.99 0.80

[0069] The data of Table 9 show the excellent stability of the cores,and confirm the total inertia of the selected excipients to SAMe and tothe other active ingredients.

EXAMPLE 6

[0070] Tablets comprising 600 mg of SAMe/tbl+vitamins B₆/B₁₂ and folicacid.

[0071] The process described in Example 5 was repeated on an industrialscale using the components and amounts (in kg) shown in the followingtable. TABLE 10 A. SAMe sulfate p-toluensulfonate 85.500 B. Vitamin B₆0.210 C. Vitamin B₁₂ 0.069 D. Folic acid 0.055 E. Calcium sulfatedihydrate 17.100 F. Calcium carbonate 2.470 G. Silica (Aerosil ®) 1.030H. Glycerol Behenate (Compritol-e-ato ®) 6.180 I. AnhydrousMicrocrystalline cellulose 6.180 L. Biogapress ® vegetal (Gattefossè)0.700 M. Labrafac ® cc (Gattefossè) 0.700 N. Shellac ® (SSB ® 63produced by G.T.C.) 2.900 O. Titanium dioxide 1.500 P. Talc 1.500 Q.Triethylcitrate 0.500 R. Iron oxide (Fe₂O₃) 0.010

[0072] The amounts refer to the preparation of a batch of 118.78 kg(68,666 tablets) for the components (A-I) concerning the preparation ofthe cores, whereas, as to coating (L-R), the amounts refer to thepreparation of a batch of 115.33 kg (66,672 tablets).

EXAMPLE 7

[0073] Tablets comprising 400 mg of SAMe/tbl+vitamins B6/B12 and folicacid.

[0074] Tablets having the composition (amounts in mg/tbl) shown in thefollowing table have been manufactured according to the processdescribed in Example 1. TABLE 11 A. SAMe sulfate p-toluensulfonate 830.0B. Vitamin B₆ 3.0 C. Vitamin B₁₂ 1.0 D. Folic acid 0.8 E. Calciumsulfate dihydrate 166.0 F. Calcium carbonate 24.0 G. Silica (Aerosil ®)10.0 H. Glycerol Behenate (Compritol-e-ato ®) 60.0 I. AnhydrousMicrocrystalline cellulose 60.0 Core Total weight 1154.8 G. Biogapress ®vegetal (Gattefossè) 7.0 H. Labrafac ® cc (Gattefossè) 7.0 I. Shellac ®(SSB ® 63 produced by G.T.C.) 30.0 L. Titanium dioxide 15.0 M. Talc 15.0N. Triethylcitrate 5.0 O. Ferric oxide (Fe₂O₃) 0.1 Tablet Total weight1233.9

[0075] However, in step 1.4, the granulate was obtained by a Ronchi AMrotative machine equipped with 18 oblong 19.0×8.8 mm punches, adjustingthe weight to 1154.80 mg/tbl and the compression strength to about 25kp.

[0076] The tablets produced had a hardness between 23 and 27 kp.

[0077] Average weight variation: 1097.06-1212.54 mg. TABLE 12 Batch no.029 stability, 400 mg SAMe/tbl cores. Batch (T/t) (K.F.) AD MTAD SAMe V.B₆ V. B₁₂ AF 029 (20/0) 1.75 0.41 1.25 412.11 3.07 1.03 0.82 029A (40/1)1.79 1.12 2.88 407.65 3.02 1.00 0.87 029B (40/3) 1.87 1.37 3.45 398.732.98 1.02 0.85 029C (40/6) 1.96 2.04 4.78 380.58 2.87 1.01 0.81

[0078] The data of Table 12 highlight the excellent stability of thecores, and confirm the total inertia of the selected excipients to SAMeand to the other active ingredients.

EXAMPLE 8

[0079] Tablets comprising 400 mg tablets of SAMe/tbl+vitamins B6/B₁₂ andfolic acid.

[0080] The process described in Example 7 was repeated on an industrialscale using components and amounts (in kg) shown in the following table.TABLE 13 A. SAMe sulfate p-toluensulfonate 85.500 B. Vitamin B₆ 0.210 C.Vitamin B₁₂ 0.069 D. Folic acid 0.055 E. Calcium sulfate dihydrate17.100 F. Calcium carbonate 2.470 G. Silica (Aerosil ®) 1.030 H.Glycerol Behenate (Compritol-e-ato ®) 6.180 I. AnhydrousMicrocrystalline cellulose 6.180 G. Biogapress ® vegetal (Gattefossè)0.700 H. Labrafac ® cc (Gattefossè) 0.700 I. Shellac ® (SSB ® 63produced by G.T.C.) 3.000 L. Titanium dioxide 1.500 M. Talc 1.500 N.Triethylcitrate 0.500 O. Ferric oxide (Fe₂O₃) 0.010

[0081] The amounts refer to the preparation of a batch of 118.78 kg(103,000 tablets) for the compounds (A-I) concerning the preparation ofthe cores, whereas, as to the coating (L-R), the amounts refer to thepreparation of a batch of 115.33 kg (100,000 tablets).

EXAMPLE 9

[0082] Tablets comprising 200 mg tablets of SAMe/tbl+500 mg ofglucosamine sulfate/tbl.

[0083] The following table illustrates the composition (amounts inmg/tbl) per each tablet obtained by the process of the invention. TABLE14 A. SAMe sulfate p-toluensulfonate 415.0 B. Glucosamine sulfate 500.0C. Calcium sulfate dihydrate 30.0 D. Calcium carbonate 12.0 E. Silica FK160 10.0 F. Glycerol Behenate (Compritol-e-ato ®) 60.0 G. AnhydrousMicrocrystalline cellulose 253.0 Core total weight 1280.0 H.Biogapress ® vegetal (Gattefossè) 7.0 I. Labrafac ® cc (Gattefossè) 7.0L. Shellac ® (SSB ® 63 produced by G.T.C.) 32.0 M. Titanium dioxide 15.0N. Talc 15.0 O. Triethylcitrate 5.0 P. Ferric oxide (Fe₂O₃) 0.1 Tablettotal weight 1361.1

[0084] Core Production:

[0085] 1.1 Blending

[0086] The environment was conditioned at a temperature of 20° C. and ata relative humidity R.H. of about 20%. In pair (A-B) (C-D) (50 mg of Fand 200 mg of G) and finally E, the components were put, in the amountsand in the order indicated in table 14, into a 200 l Viani biconicalmixer, blending each group of compounds for about 10 minutes. Silica wasfinally added and blended for further 10 minutes then transferring forfurther 10 minutes the resulting mixture into dry containers, whilecontrolling both humidity and temperature.

[0087] 1.2 Precompression: according to what described in Example 1

[0088] 1.3. Granulation and blending

[0089] The tablets resulting from the previous step were granulated on a1200 μm net, while checking the humidity. Then, the resulting granulatewas blended again, into a 200 l Viani mixer, with the remaining amountsof microcrystalline cellulose and Compritol-e-ato® (53 and 10 mgrespectively).

[0090] 1.4 Compression

[0091] The final compression of the granulate was carried out by aRonchi AM rotative machine, equipped with 18 oblong 19.0×8.8 mm punches,adjusting the weight to 1280.8 mg/tbl and the compression strength toabout 25 kp. The produced tablets showed a hardness between 23 and 27kp.

[0092] Average weight variation: 1216.0-1344.0 mg

[0093] Friability, humidity and standard yield were found to conform towhat illustrated in Example 1. TABLE 15 Batch no. 032 stability, 200 mgSAMe/tbl cores Batch (T/t) (K.F.) AD MTAD SAMe S.G. 032 (20/0) 1.38 0.341.52 217.98 502.06 032A (40/1) 1.26 1.01 3.78 215.42 501.94 032B (40/3)1.15 1.23 4.89 205.52 500.12 032C (40/6) 1.32 2.02 5.98 200.47 501.45

[0094] The data in Table 15 highlight the excellent stability of thecores, and confirm the total inertia of the selected excipients to SAMeand to glucosamine sulfate.

[0095] The protection of the cores and the gastroresistant filming werecarried out according to that described in Example 1.

EXAMPLE 10

[0096] Tablets comprising 200 mg of SAMe/tbl+500 mg of glucosaminesulfate/tbl.

[0097] The process described in Example 9 was repeated on an industrialscale using components and amounts (in kg) shown in the following table.TABLE 16 A. SAMe sulfate p-toluensulfonate 42.74 B. Glucosamine sulfate51.50 C. Calcium Sulfate Dihydrate 3.09 D. Calcium Carbonate 1.23 E.Silica FK 160 1.03 F. Glycerol Behenate(Compritol-e-ato ®) 6.18 G.Anhydrous Microcrystalline Cellulose 26.06 H. Biogapress ® vegetal(Gattefossè) 0.70 I. Labrafac ® cc (Gattefossè) 0.70 L. Shellac ® (SSB ®63 produced by G.T.C.) 3.20 M. Titanium dioxide 1.50 N. Talc 1.50 O.Triethylcitrate 0.50 P. Iron oxide (Fe₂O₃) 0.01

[0098] The amounts refer to the preparation of a batch of 131.8 kg(103,000 tablets) for the components (A-G) concerning the preparation ofthe cores, whereas as to the coating (H-P), the amounts refer to thepreparation of a batch of 128.0 kg (100,000 tablets).

EXAMPLE 11

[0099] Tablets comprising 200 mg of SAMe/tbl+500 mg ofmethylsulfonylmethane (MSM)/tbl

[0100] Tablets having the composition (amounts in g/tbl) shown in thefollowing table according to the details described in Example 1. TABLE17 A. SAMe sulfate p-toluensulfonate 415.0 B. MSM 500.0 C. Calciumsulfate dihydrate 30.0 D. Calcium carbonate 12.0 E. Silica FK 160 10.0F. Glycerol Behenate (Compritol-e-ato ®) 60.0 G. AnhydrousMicrocrystalline cellulose 253.0 Core total weight 1280.0 H.Biogapress ® vegetal (Gattefossè) 7.0 I. Labrafac ® cc (Gattefossè) 7.0L. Shellac ® (SSB ® 63 produced by G.T.C.) 32.0 M. Titanium dioxide 15.0N. Talc 15.0 O. Triethylcitrate 5.0 P. Ferric oxide (Fe₂O₃) 0.1 TabletTotal weight 1361.1

[0101] However, the blending and granulation steps were carried outaccording to what described in Example 9, whereas the compression of thegranulate was carried out by a Ronchi AM rotative machine equipped with18 oblong 19.0×8.8 mm punches, adjusting the weight to 1280.0 mg/tbl andthe compression strength to about 25 kp. The produced tablets showed ahardness between 23 and 27 kp. Average weight variation: 1216.0-1344.0mg. TABLE 18 Batch no. 035 stability, 200 mg SAMe/tbl cores Batch (T/t)K.F) AD MTAD SAMe MSM 035 (20/0) 1.42 0.40 1.36 210.23 500.12 035A(40/1) 1.35 1.45 2.99 203.58 501.45 035B (40/3) 1.74 1.73 3.75 201.86496.56 035C (40/6) 1.15 2.52 4.12 194.63 498.01

[0102] The data in Table 18 show the excellent stability of the cores,and confirm the total inertia of the selected excipients as to SAMe andto glucosamine sulfate.

EXAMPLE 12

[0103] Tablets comprising 200 mg of SAMe/tbl+500 mg ofmethylsulfonylmethane (MSM)/tbl

[0104] The process described in Example 11 was repeated on an industrialscale using the components and amounts (in kg) shown in the followingtable. TABLE 19 A. SAMe sulfate p-toluensulfonate 42.74 B.Metilsulfonilmethane MSM 51.50 C. Calcium sulfate dihydrate 3.09 D.Calcium carbonate 1.23 E. Silica FK 160 1.03 F. Glycerol Behenate(Compritol-e-ato ®) 6.18 G. Anhydrous Microcrystalline cellulose 26.06H. Biogapress ® vegetal (Gattefossè) 0.70 I. Labrafac ® cc (Gattefossè)0.70 L. Shellac ® (SSB ® 63 produced by G.T.C.) 3.20 M. Titanium dioxide1.50 N. Talc 1.50 O. Triethylcitrate 0.50 P. Ferric oxide (Fe₂O₃) 0.01

[0105] The amounts refer to the preparation of a batch of 131.8 kg(103,000 tablets) for the components (A-G) concerning the preparation ofthe cores whereas, the amounts regarding the coating (H—P) refer to thepreparation of a batch of 128.0 kg (100,000 tablets).

EXAMPLE 13

[0106] Tablets comprising 200 mg of SAMe ion/tbl+400 mg of chondroitinsulfate

[0107] Tablets having the composition (amounts in g/tbl) shown in thefollowing table were produced according to what described in Example 1.TABLE 20 A. SAMe sulfate p-toluensulfonate 415.0 B. Chondroitin sulfate400.0 C. Calcium sulfate dihydrate 123.0 D. Calcium carbonate 12.0 E.Silica FK 160 10.0 F. Glycerol Behenate (Compritol-e-ato ®) 60.0 G.Anhydrous Microcrystalline cellulose 130.0 Core total weight 1150.0 H.Biogapress ® vegetal (Gattefossè) 7.0 I. Labrafac ® cc (Gattefossè) 7.0L. Shellac ® (SSB ® 63 produced by G.T.C.) 30.0 M. Titanium dioxide 15.0N. Talc 15.0 O. Triethylcitrate 5.0 P. Ferric oxide (Fe₂O₃) 0.1 TabletTotal weight 1229.1

[0108] However, in step 1.4, the granulate was compressed by a Ronchi AMrotative machine equipped with 18 oblong 19.0×8.8 mm punches, adjustingthe weight to 1150 mg/tbl and the compression strength to about 25 kp.The produced tablets showed a hardness between 23 and 27 kp.

[0109] Average weight variation: 1092.5-1207.5 mg TABLE 21 Batch no. 038stability, 200 mg SAMe/tbl cores Batch (T/t) K.F. AD MTAD SAMe SC 038(20/0) 2.12 0.33 1.26 214.89 398.85 038A (40/1) 2.24 1.55 2.25 208.36396.44 038B (40/3) 2.09 1.78 3.36 202.12 397.36 038C (40/6) 1.97 2.694.42 198.78 393.45

[0110] The data in Table 21 show the excellent stability of the cores,and confirm the total inertia of the selected excipients as to SAMe andto chondroitin sulfate.

EXAMPLE 14

[0111] Tablets comprising 200 mg of SAMe/tbl+400 mg of chondroitinsulfate/tbl

[0112] The process described in Example 13 was repeated on an industrialscale using the components and amounts (in kg) shown in the followingtable. TABLE 22 A. SAMe solfate p-toluensulfonate 42.74 B. Chondroitinsulfate 41.20 C. Calcium sulfate dihydrate 12.67 D. Calcium carbonate1.23 E. Silica FK 160 1.03 F. Glycerol Behenate (Compritol-e-ato ®) 6.18G. Anhydrous Microcrystalline cellulose 13.39 H. Biogapress ® vegetal(Gattefossè) 0.70 I. Labrafac ® cc (Gattefossè) 0.70 L. Shellac ® (SSB ®63 produced by G.T.C.) 3.00 M. Titanium dioxide 1.50 N. Talc 1.50 O.Triethylcitrate 0.50 P. Ferric oxide (Fe₂O₃) 0.01

[0113] The amounts refer to the preparation of a batch of 118.45 kg(103,000 tablets) for the components (A-G) concerning the preparation ofthe core, whereas, the amounts regarding the coating (H-P) refer to thepreparation of a batch of 115.00 kg (100,000 tablets).

EXAMPLE 15

[0114] Tablets comprising 200 mg of SAMe/tbl+400 mg of chondroitinsulfate/tbl+500 mg glucosamine sulfate/tbl.

[0115] The following table shows the composition (amounts in mg/tbl) pereach tablet obtained by the process of the invention. TABLE 23 A. SAMesulfate p-toluensulfonate 415.0 B. Chondroitin sulfate 400.0 C.Glucosamine sulfate 500.0 D. Calcium sulfate dihydrate 20.0 E. Calciumcarbonate 12.0 F. Silica FK 160 15.0 G. Glycerol Behenate(Compritol-e-ato ®) 70.0 H. Anhydrous Microcrystalline cellulose 268.0Core total weight 1700.0 I. Biogapress ® vegetal (Gattefossè) 10.0 L.Labrafac ® cc (Gattefossè) 10.0 M. Shellac ® (SSB ® 63 produced byG.T.C.) 42.5 N. Titanium dioxide 21.0 O. Talc 21.0 P. Triethylcitrate7.5 Q. Ferric oxide (Fe₂O₃) 0.1 Tablet Total weight 1811.6

[0116] Core Production:

[0117] 1.1. Blending

[0118] The environment was conditioned at a temperature of 20° C. and ata relative humidity of about 20% R.H. The (A,B,C), (D,E) and (60 mg of Gand 200 mg of H) and finally E components, in the amounts and in theorder indicated in table 23, were put into a 200 l Viani biconicalmixer, blending each group of substances for about 10 minutes. Finallythe silica was added and blended for further 10 minutes putting theresulting mixture into dry containers, always checking both humidity andtemperature.

[0119] 1.2. Precompression: according to what described in Example 1

[0120] 1.3 Granulation and Blending

[0121] The tablets obtained during the first process step weregranulated on a 1200 μm net in a controlled humidity environment. Then,in the 200 l Viani mixer, the obtained granulate was blended again withthe remaining amounts of microcrystalline cellulose and compritol-e-ato®(68 and 10 mg, respectively)

[0122] 1.4 Compression

[0123] The final compression of the granulate was carried out by aRonchi AM rotative machine equipped with 18 mm oblong 23.6×10.8 mmpunches, adjusting the weight to 1700 mg/tbl and the compressionstrength to about 25 kp. The produced tablets showed a hardness between23 and 27 kp.

[0124] Average weight variation: 1615.0-1785.0 mg Friability, humidityand standard yield resulted to be in accordance with Example 1. TABLE 24Batch no. 041 stability, 200 mg SAMe/tbl cores Batch (T/t) K.F. AD MTADSAMe MSM SC 041 (20/0) 1.97 0.25 1.11 232.78 506.06 400.05 041A (40/1)1.75 0.85 3.00 226.23 500.94 402.14 041B (40/3) 1.56 1.12 3.89 219.56496.78 398.85 041C (40/6) 2.00 2.00 4.89 214.59 499.77 397.56

[0125] The data in Table 24 show the excellent stability of the cores,and confirm the total inertia of the selected excipients as to SAMe andto the other active ingredients.

EXAMPLE 16

[0126] Tablets comprising 200 mg of SAMe/tbl+400 mg of chondroitinsulfate/tbl+500 mg of glucosamine sulfate/cpr.

[0127] The process described in Example 15 was repeated on an industrialscale using the components and amounts (in kg) shown in the followingtable. TABLE 25 A. SAMe sulfate p-toluensulfonate 29.900 B. Chondroitinsulfate 28.820 C. Glucosamine sulfate 36.030 D. Calcium sulfatedihydrate 1.440 E. Calcium carbonate 0.860 F. Silica FK 160 1.080 G.GlycerolBehenate (Compritol-e-ato ®) 5.040 H. Anhydrous Microcrystallinecellulose 19.300 I. Biogapress ® vegetal (Gattefossè) 0.700 L.Labrafac ® cc (Gattefossè) 0.700 M. Shellac ®(SSB ® 63 produced byG.T.C.) 2.970 N. Titanium dioxide 1.470 O. Talc 1.470 P. Triethylcitrate0.520 Q. Ferric oxide (Fe₂O₃) 0.007

[0128] The amounts refer to the preparation of a batch of 122.57 kg(72,100 tablets) for the components (A-H) concerning the preparation ofthe core whereas, as to the coating (1-Q), the amounts refer to thepreparation of a batch of 119.00 kg (70,000 tablets).

[0129] Stability Trials on The Finished Product

[0130] The stability of the compositions obtainable by the process ofthe invention and referring to the above mentioned odd examples both at40° C. and 75% R.H. (STRESS TEST) and at long-term room temperature(SHELF LIFE), were evaluated on the basis of their aspect change(mainly, colour change), titre (mg/tbl) of the SAMe ion and of the otheractive ingredients, humidity increase (K.F.) and impurities due to SAMedegradation; the presence of possible degradation products,substantially adenosine and mehtylthioadenosine, expressed aspercentages to the weight of SAMe sulfate p-toluensulfonate per tablet,was further controlled by HPLC.

[0131] Stress Test

[0132] The tablets have been packed in closed and sealed glass bottlesso as to simulate the final packaging (usually, aluminium/aluminiumblister).

[0133] The samples thus prepared, were kept in a oven (Kottermann) for aperiod of six months, thermostated at 40±2° C. 75% R.H.

[0134] Nine samples from three different batches were used for the 200mg tablets (Es. 3, 9, 11, 13, 15) and further nine samples from threedifferent batches were used for the 400 and 600 mg tablets (Ex. 1, 5, 7)wherein for each sample, any batch was sampled after 0,1, 3, and 6months. TABLE 26 Batch no. 023- 400 mg SAMe/tbl tablets (EX. 1) Batch(T/t) K.F. AD MTAD SAMe 023 (20/0) 1.78 0.31 1.16 422.42 023A(40/1) 1.861.14 1.45 411.19 023B(40/3) 1.85 1.95 3.44 399.12 023C(40/6) 1.89 2.243.89 384.67

[0135] TABLE 27 Batch no. 024- 400 mg SAMe/tbl tablets (EX. 1) Batch(T/t) (K.F.) AD MTAD SAMe 024 (20/0) 1.86 0.31 1.27 423.93 024A (40/1)1.91 1.05 1.89 409.78 024B (40/3) 1.59 1.72 3.37 395.37 024C (40/6) 1.811.84 4.53 385.67

[0136] TABLE 28 Batch no. 025- 400 mg SAMe/tbl tablets (EX. 1) Batch(T/t) (K.F.) AD MTAD SAMe 025 (20/0) 1.70 0.47 1.42 423.51 025A (40/1)1.76 1.04 2.35 415.19 025B (40/3) 1.85 1.78 3.36 411.36 025C (40/6) 1.732.82 3.20 381.58

[0137] TABLE 29 Batch no. 015 stability, 200 mg SAMe/tbl tablets (EX. 3)Batch (T/t) (K.F.) AD MTAD SAMe 015 (20/0) 1.89 0.42 2.08 240.60 015A(40/1) 1.98 1.81 5.05 233.9 015B (40/3) 2.23 1.78 6.05 218.62 015C(40/6) 1.62 2.54 6.41 227.51

[0138] TABLE 30 Batch no. 017- 200 mg SAMe/tbl tablets (EX. 3) Batch(T/t) (K.F.) AD MTAD SAMe 017 (20/0) 2.11 0.34 1.56 216.22 017A (40/1)2.18 1.55 2.89 213.43 017B (40/3) 2.08 1.63 5.45 199.16 017C (40/6) 1.812.21 6.79 193.21

[0139] TABLE 31 Batch no. 018- 200 mg SAMe/tbl tablets (EX. 3) Batch(T/t) (K.F.) AD MTAD SAMe 018 (20/0) 1.65 0.29 1.83 211.20 018A (40/1)1.95 1.04 2.55 202.30 018B (40/3) 1.77 1.88 3.36 196.25 018C (40/6) 1.652.35 4.45 190.20

[0140] TABLE 32 Batch no. 026 stability, 600 mg SAMe/tbl tablets (EX. 5)Batch (T/t) K.F. AD MTAD SAMe V. B₆ V. B₁₂ AF 026 (20/0) 2.22 0.39 1.22630.56 3.07 1.03 0.83 26A (40/1) 2.05 1.48 3.23 615.45 2.97 1.00 0.8526B (40/3) 2.18 1.97 4.52 601.25 2.89 1.02 0.80 26C (40/6) 2.27 2.884.99 577.22 2.75 0.99 0.79

[0141] TABLE 33 Batch no. 027- 600 mg SAMe/tbl tablets (EX. 5) Batch(T/t) K.F. AD MTAD SAMe V. B₆ V. B₁₂ AF 027 (20/0) 1.58 0.55 1.57 627.673.10 1.10 0.89 27A (40/1) 1.57 1.31 3.15 602.99 3.05 1.04 0.84 27B(40/3) 1.97 1.99 4.72 589.11 2.96 1.07 0.80 27C (40/6) 2.17 2.77 5.86571.98 2.87 1.01 0.85

[0142] TABLE 34 Batch 028- 600 mg SAMe/tbl tablets (EX. 5) Folic Batch(T/t)¹ K.F. AD MTAD SAMe V. B₆ V. B₁₂ Ac.  028 (20/0) 2.05 0.44 1.28635.88 3.03 1.02 0.80 028A (40/1) 1.85 1.60 2.55 613.89 2.99 1.02 0.79028B (40/3) 1.97 1.79 3.99 602.12 2.89 1.00 0.80 028C (40/6) 2.22 2.554.89 582.47 2.70 0.95 0.74

[0143] TABLE 35 Batch no. 029 stability, 400 mg SAMe/tbl tablets (EX. 7)Folic Batch (T/t)¹ K.F. AD MTAD SAMe V. B₆ V. B₁₂ Ac.  029 (20/0) 1.950.31 1.42 415.91 3.01 1.02 0.82 029A (40/1) 2.02 1.52 2.58 409.35 2.891.01 0.85 029B (40/3) 1.98 1.77 3.12 400.45 2.98 1.07 0.80 029C (40/6)2.12 2.84 4.69 380.11 2.80 0.97 0.84

[0144] TABLE 36 Batch no. 030- 400 mg SAMe tablets/tbl (EX. 7) FolicBatch (T/t)¹ K.F. AD MTAD SAMe V. B₆ V. B₁₂ Ac. 030 (20/0) 2.05 0.551.59 421.01 3.11 1.01 0.79 030A (40/1) 2.10 1.26 2.96 414.58 3.11 1.000.81 030B (40/3) 1.99 1.75 3.78 401.69 3.05 1.02 0.78 030C (40/6) 1.952.58 5.25 382.56 2.89 0.97 0.80

[0145] TABLE 37 Batch no. 031- 400 mg SAMe/tbl tablets (EX. 7) FolicBatch (T/t)¹ K.F. AD MTAD SAMe V. B₆ V. B₁₂ Ac. 031 (20/0) 1.87 0.471.72 417.56 3.12 1.04 0.80 031A (40/1) 1.79 1.56 2.89 409.78 3.08 1.010.81 031B (40/3) 1.97 1.99 3.75 402.32 3.01 0.96 0.84 031C (40/6) 2.012.45 4.96 386.81 2.96 0.95 0.78

[0146] TABLE 38 Batch no. 032 stability, 200 mg SAMe/tbl tablets (EX. 9)Batch (T/t)¹ K.F. AD MTAD SAMe SG 032 (20/0) 1.11 0.27 1.42 210.23503.16 032A (40/1) 1.21 0.69 2.15 208.56 506.01 032B (40/3) 1.36 1.533.89 202.37 504.56 032C (40/6) 1.19 2.56 4.12 188.59 502.89

[0147] TABLE 39 Batch no. 033- 200 mg SAMe/tbl tablets (EX. 9) Batch(T/t)¹ K.F. AD MTAD SAMe SG 033 (20/0) 1.24 0.59 1.36 212.26 504.52 033A(40/1) 1.32 0.96 2.66 207.59 506.74 033B (40/3) 1.21 1.56 3.89 193.73504.16 033C (40/6) 1.19 2.59 5.03 190.47 500.11

[0148] TABLE 40 Batch 034- 200 mg SAMe/tbl tablets (EX. 9) Batch (T/t)¹K.F. AD MTAD SAMe SG 034 (20/0) 1.16 0.74 1.32 220.22 501.12 034A (40/1)1.47 1.51 2.78 212.43 507.55 034B (40/3) 1.01 1.83 3.75 204.24 509.56034C (40/6) 1.27 2.82 4.37 198.26 503.44

[0149] TABLE 41 Batch no. 035 stability, 200 mg SAMe/tbl tablets (EX.11) Batch (T/t)¹ K.F. AD MTAD SAMe MSM. 035 (20/0) 1.27 0.34 1.65 208.54500.44 035A (40/1) 1.39 1.11 2.45 207.12 508.42 035B (40/3) 1.46 1.533.24 198.55 501.22 035C (40/6) 1.05 2.28 4.75 189.44 489.82

[0150] TABLE 42 Batch no. 036- 200 mg SAMe/tbl tablets (EX. 11) Batch(T/t) K.F. AD MTAD SAMe MSM 036 (20/0) 1.20 0.77 1.44 213.43 501.47 035A(40/1) 1.17 1.45 2.57 209.33 502.91 036B (40/3) 1.57 1.83 3.46 202.36500.11 036C (40/6) 1.28 2.60 4.27 194.10 492.00

[0151] TABLE 43 Batch no. 037- 200 mg SAMe/tbl tablets (EX. 11) Batch(T/t) K.F. AD MTAD SAMe MSM 037 (20/0) 1.42 0.44 1.54 211.81 502.57 037A(40/1) 1.54 1.01 2.00 208.37 507.54 037B (40/3) 1.30 1.27 3.01 201.16505.22 037C (40/6) 1.55 1.89 3.79 197.73 501.10

[0152] TABLE 44 Batch no. 038 stability, 200 mg SAMe/tbl tablets (EX.13) Batch (T/t)¹ K.F. AD MTAD SAMe SC 038 (20/0) 2.19 0.54 1.56 212.42403.36  038 (40/1) 2.05 1.65 2.89 204.67 402.98 038B (40/3) 2.12 1.963.37 200.21 400.75 038C (40/6) 1.93 2.67 4.92 193.87 397.64

[0153] TABLE 45 Batch no. 039- 200 mg SAMe/tbl tablets (EX. 13) Batch(T/t)¹ K.F. AD MTAD SAMe SC 039 (20/0) 2.01 0.47 1.02 209.55 402.42 039(40/1) 2.27 1.05 2.32 204.65 399.37 039B (40/3) 2.32 1.83 4.14 196.44397.97 039C (40/6) 2.12 2.71 5.34 189.81 398.71

[0154] TABLE 46 Batch no. 040- 200 mg SAMe/tbl tablets (EX. 13) Batch(T/t)¹ K.F. AD MTAD SAMe SC  040 (20/0) 2.21 0.24 1.23 217.37 402.91 040 (40/1) 1.87 1.15 1.74 214.28 399.39 040B (40/3) 2.04 1.37 2.69205.19 401.26 040C (40/6) 2.17 2.02 3.18 201.73 391.94

[0155] TABLE 47 Batch no. 041 stability, 200 mg SAMe/tbl tablets (EX.15) Batch (T/t)¹ K.F. AD MTAD SAMe MSM SC  041 (20/0) 1.88 0.51 1.71205.15 503.32 402.56 041A (40/1) 2.02 0.97 2.58 200.67 504.54 401.84041B (40/3) 1,85 1.42 3.42 194.34 503.18 399.11 041C (40/6) 2.04 1.974.31 190.41 504.74 397.41

[0156] TABLE 48 Batch no. 042- 200 mg SAMe/tbl tablets (EX. 15) Batch(T/t)¹ K.F. AD MTAD SAMe MSM SC  042 (20/0) 1.72 0.45 1.64 223.54 502.64404.35 042A (40/1) 1.97 0.93 2.25 217.96 507.55 401.42 042B (40/3) 1.961.44 3.34 211.14 498.43 400.36 042C (40/6) 2.16 2.13 4.03 204.37 494.41402.33

[0157] TABLE 49 Batch no. 043- 200 mg SAMe/tbl tablets (EX. 15) Batch(T/t)¹ K.F. AD MTAD SAMe MSM SC  043 (20/0) 1.97 0.35 1.43 213.28 503.56402.73 043A (40/1) 1.94 1.02 2.56 206.55 496.94 403.65 043B (40/3) 1.861.52 3.36 202.43 498.67 403.85 043C (40/6) 2.04 2.32 4.23 195.68 494.47401.19

[0158] By the stability data obtained at 40° C. and 75% R.H (stresstest), it can be noted that all batches tested showed after six months adegradation lower than 10% both for SAMe and for the other activeingredients.

[0159] Comparative Stress Tests

[0160] The following tables show the stress test results, at 40° C. and75% R.H. during a period of three months, carried out on two batches oftablets prepared according to the example no. 3, and the results of thestress test carried out on the same tablets after exposing them, for aperiod of 7 days, at 40° C. and 50% R.H. The samples were kept, over thethree month-testing period, into closed and sealed glass bottles inorder to silmulate the final packaging into aluminium blisters. TABLE 50Batch no. 017-200 mg SAMe/tbl tablets, protected by Biogapress ® vegetaland Labrafac ®cc. Batch (T/t)¹ K.F. AD MTAD SAMe 03179 (20/0) 2.11 0.341.56 216.22 03179A (40/1) 2.18 1.55 2.89 213.43  017B (40/3) 2.08 1.635.45 199.16

[0161] TABLE 51 (comparison) Batch no. 018- 200 mg SAMe/tbl tablets,without the protection of Biogapress ® vegetal and Labrafac ®cc, butdesiccated before undergoing gastroresistant film coating. Batch (T/t)¹K.F. AD MTAD SAMe 03181 (20/0) 1.65 0.29 1.83 211.20 03179A (40/1) 1.951.04 2.55 202.30  017B (40/3) 1.77 1.88 3.36 196.25

[0162] TABLE 52 Batch no. 017-200 mg SAMe/tbl tablets, protected byBiogapress ® vegetal and Labrafac ®cc and exposed to 40° C. and 50% R.H.Batch (T/t)¹ K.F. AD MTAD SAMe 03179 (20/0) 2.11 0.34 1.56 216.22 03179A(40/1) 2.79 1.95 3.09 200.23  0317B (40/3) 2.81 4.04 6.51 180.63

[0163] TABLE 53 (comparison) Batch no. 018- 200 mg SAMe/tbl tablets,without Biogapress ® vegetal and Labrafac ®cc protection, desiccatedbefore undergoing gastroresistant film coating and exposed at 40° C. and50% R.H. for 7 days. Batch (T/t)¹ K.F. AD MTAD SAMe 03181 (20/0) 1.650.29 1.83 211.20 018A (40/1) 4.85 7.04 4.15 166.63 03181B (40/3) 4.6218.85 6.98 118.72

[0164] The results showed in the latest four tables, as those ones shownin the previous tables relating to the stress test show the highstability and the low hygroscopicity of the tablets obtainable by theprocess of the invention.

[0165] As a further confirmation of the results obtainable by carryingout the invention, the product Samyr® (Knoll) 200 mg SAMe/tbltablets—batch no. 125—was bought to comparatively evaluate it against asample of the tablets obtainable by the process of the invention (batch017-200 mg SAMe/tbl tablets coated by Biogapress® vegetal andLabrafac®cc, example 3); both batches were exposed at a temperature of40° C. and at 75% R.H1., for 7 days. TABLE 54 Batch (T/t) K.F. AD MTADSAMe 03179 (20/) 2.01 0.37 1.54 210.15 03179A (55/3) 2.39 1.85 2.89201.25 03181B (55/7) 2.79 4.15 5.81 182.75

[0166] TABLE 55 (comparison) Batch (T/t) K.F. AD MTAD SAMe 125 (20/)1.75 0.34 1.12 209.12 125A (55/3) 3.01 6.48 4.41 176.15 125B (55/7) 4.7717.41 7.14 129.42

[0167] According to the data in the latest two tables, it can be notedthat the tablets obtainable by the process of the invention show ahumidity increase four times lower and are, therefore, four times lesshygroscopic than the commercialised tablets used for the comparison; thetablets obtainable by the process of the invention result therefore tobe more stable (for example, the AD amount at a temperature of 55° C.after 7 days, is more than four times higher in the case of Samyr® thanthe tablets of the invention) even after accidental exposures toenvironmental humidity, due, for example, to microfractures of thealuminium blisters wherein the tablets are usually packed.

[0168] Shelf Life

[0169] The tablets were packed in closed and sealed glass bottles so asto simulate the final packaging conditions (generally, in aluminiumblisters).

[0170] The samples were selected according to the same method andamounts described for the stress test and preserved in a thermostatedenvironment at a temperature of 25±2° C. and at 60% R.H.

[0171] Nine samples from three different batches were used for the 200mg tablets (Ex. 3, 9, 11, 13, 15) and further nine samples from threedifferent batches were used for the 400 mg tablets (Ex. 1, 5, 7) whereineach sample, of every single batch, was sampled after 0, 3, 6, 12, 24and 36 months. TABLE 56 Batch no. 023- 400 mg SAMe/tbl tablets (EX. 1)Batch (T/t) K.F. AD MTAD SAMe  023 (20/0) 1.78 0.31 1.16 422.42 023A(25/3) 1.79 0.42 1.11 423.85 023B (25/6) 1.82 0.56 1.23 129.42 023C(25/12) 1.82 0.55 1.57 416.32

[0172] TABLE 57 Batch no. 024- 400 mg SAMe/tbl tablets (EX. 1) Batch(T/t) K.F. AD MTAD SAMe  024 (20/0) 1.86 0.31 1.27 423.93 024A (25/3)1.72 0.39 1.25 420.56 024B (25/6) 1.65 0.49 1.44 421.76 024C (25/12)1.87 0.75 1.69 414.34

[0173] TABLE 58 Batch no. 025- 400 mg SAMe/tbl tablets (EX. 1) Batch(T/t) K.F. AD MTAD SaMe  025 (20/0) 1.70 0.47 1.42 423.51 025A (25/3)1.87 0.58 1.49 416.45 025B (25/6) 2.09 0.94 1.62 419.91 025C (25/12)1.93 1.02 1.77 415.37

[0174] TABLE 59 Batch no. 015- 200 mg SAMe/tbl tablets (EX. 3) Batch(T/t)¹ K.F. AD MTAD SAMe  015 (20/0) 1.89 0.42 2.08 240.60 015A (25/3)1.75 0.51 2.05 233.19 015B (25/6) 2.01 0.55 1.95 218.62 015C (25/12)1.82 0.64 2.41 227.51

[0175] TABLE 60 Batch no. 017- 200 mg SAMe/tbl tablets (EX. 3) Batch(T/t)¹ K.F. AD MTAD SAMe  017 (20/0) 2.11 0.34 1.56 216.22 017A (25/3)1.82 0.29 1.69 217.83 017B (25/6) 1.79 0.38 1.68 215.46 017C (25/12)1.86 0.49 1.77 211.12

[0176] TABLE 61 Batch no. 018, 200 mg SAMe/tbl tablets (EX. 3) Batch(T/t)¹ K.F. AD MTAD SAMe  018 (20/0) 1.65 0.29 1.83 211.20 018A (25/3)1.55 0.24 2.05 212.00 018B (25/6) 1.83 0.37 2.12 208.67 018C (25/12)1.94 0.75 2.16 204.22

[0177] TABLE 62 Batch no. 026, 600 mg SAMe/tbl tablets (EX. 5) Batch(T/t)¹ K.F. AD MTAD SAMe V. B₆ V. B₁₂ FA  026 (20/0) 2.22 0.39 1.22630.56 3.07 1.03 0.83 026A (25/3) 1.95 0.38 1.37 627.95 3.05 1.06 0.82026B (25/6) 2.03 0.57 1.51 621.15 2.98 1.01 0.82 026C (25/12) 1.83 0.851.69 615.37 2.86 0.98 0.78

[0178] TABLE 63 Batch no. 027, 600 mg SAMe/tbl tablets (EX. 5) Batch(T/t)¹ K.F. AD MTAD SAMe V. B₆ V. B₁₂ FA  027 (20/0) 1.58 0.55 1.57627.67 3.10 1.10 0.89 027A (25/3) 1.66 0.49 1.65 620.63 2.95 1.07 0.80027B (25/6) 1.73 0.59 1.64 608.71 3.03 1.06 0.84 027C (25/12) 1.78 0.641.84 603.52 3.02 1.03 0.83

[0179] TABELLA 64 Batch no. 028, 600 mg SAMe/tbl tablets (EX. 5) Batch(T/t)¹ K.F. AD MTAD SAMe V. B₆ V. B₁₂ FA  028 (20/0) 2.05 0.44 1.28635.88 3.03 1.02 0.80 028A (25/3) 1.96 0.57 1.33 627.26 2.87 1.00 0.81028B (25/6) 1.77 0.63 1.37 620.21 2.96 0.96 0.80 028C (25/12) 2.02 1.021.79 613.34 2.90 0.96 0.78

[0180] TABLE 65 Batch 029- 400 mg SAMe/tbl tablets (EX. 7) Batch (T/t)¹K.F. AD MTAD SAMe V. B₆ V. B₁₂ FA  029 (20/0) 1.95 0.31 1.42 415.91 3.011.02 0.82 029A (25/3) 1.99 0.52 1.58 416.76 3.00 0.98 0.83 029B (25/6)1.78 0.47 1.67 413.45 2.97 1.01 0.82 029C (25/12) 2.01 0.84 1.79 403.112.88 0.99 0.78

[0181] TABELLA 66 Batch no. 030, 400 mg SAMe/tbl tablets (EX. 7) Batch(T/t)¹ K.F. AD MTAD SAMe V. B₆ V. B₁₂ FA  030 (20/0) 2.05 0.55 1.59421.01 3.11 1.01 0.79 030A (25/3) 2.02 0.56 1.96 418.37 3.03 0.98 0.80030B (25/6) 1.89 0.75 1.88 419.11 3.05 1.03 0.78 030C (25/12) 2.09 0.981.95 408.33 2.97 0.98 0.78

[0182] TABELLA 67 Batch no. 031, 400 mg SAMe/tbl tablets (EX. 7) Batch(T/t)¹ K.F. AD MTAD SAMe V. B₆ V. B₁₂ FA  031 (20/0) 1.87 0.47 1.72417.56 3.12 1.04 0.80 031A (25/3) 1.79 0.50 1.89 419.00 3.03 1.02 0.79031B (25/6) 1.83 0.69 1.95 413.23 3.04 0.97 0.82 031C (25/12) 1.68 0.882.16 402.18 3.01 0.97 0.77

[0183] TABLE 68 Batch no. 032- 200 mg SAMe/tbl tablets (EX. 9) Batch(T/t)¹ K.F. AD MTAD SAMe SG  032 (20/0) 1.11 0.27 1.42 210.23 503.16032A (25/3) 0.96 0.38 1.38 212.00 502.01 032B (25/6) 1.12 0.69 1.86207.11 503.56 032C (25/12) 1.29 0.87 2.03 205.19 499.89

[0184] TABLE 69 Batch no. 033, 200 mg SAMe/tbl tablets (EX. 9) Batch(T/t)¹ K.F. AD MTAD SAMe SG  033 (20/0) 1.24 0.59 1.36 212.26 504.52033A (25/3) 1.02 0.56 1.43 209.54 501.47 033B (25/6) 1.21 0.76 1.68210.26 500.76 033C (25/12) 1.33 1.09 1.83 208.73 496.17

[0185] TABLE 70 Batch no. 034, 200 mg SAMe/tbl tablets (EX. 9) Batch(T/t)¹ K.F. AD MTAD SAMe SG  034 (20/0) 1.16 0.74 1.32 220.22 501.12034A (25/3) 1.23 0.81 1.28 218.35 498.33 034B (25/6) 1.08 0.83 1.35219.73 499.16 034C (25/12) 1.17 0.98 1.67 216.13 496.83

[0186] TABLE 71 Batch no. 035, 200 mg SAMe/tbl tablets (EX. 9) Batch(T/t)¹ K.F. AD MTAD SAMe MSM  035 (20/0) 1.27 0.34 1.65 208.54 505.44035A (25/3) 1.33 0.41 1.87 210.17 501.26 035B (25/6) 1.26 0.63 1.97206.76 502.16 035C (25/12) 1.05 0.84 2.15 202.44 497.87

[0187] TABLE 72 Batch no. 036, 200 mg SAMe/tbl tablets (EX. 11) Batch(T/t)¹ K.F. AD MTAD SAMe MSM  036 (20/0) 1.20 0.77 1.44 213.43 501.4036A (25/3) 1.35 0.85 1.57 209.73 501.19 036B (25/6) 1.13 0.97 1.76211.12 496.71 036C (25/12) 1.24 1.02 1.97 206.34 497.05

[0188] TABLE 73 Batch no. 037, 200 mg SAMe/tbl tablets (EX. 11) Batch(T/t)¹ K.F. AD MTAD SAMe MSM  037 (20/0) 1.42 0.44 1.54 211.81 502.57037A (25/3) 1.27 0.68 1.86 209.44 498.14 037B (25/6) 1.30 1.01 2.01205.16 500.76 037C (25/12) 1.52 1.09 2.39 201.53 497.12

[0189] TABLE 74 Batch 038- 200 mg SAMe/tbl tablets (EX. 13) Batch (T/t)¹K.F. AD MTAD SAMe SC  038 (20/0) 2.19 0.54 1.56 212.42 403.36 038A(25/3) 2.03 0.49 1.59 212.56 401.42 038B (25/6) 2.23 0.63 1.71 211.89401.18 038C (25/12) 2.30 0.84 1.82 208.13 398.74

[0190] TABLE 75 Batch no. 039- 200 mg SAMe/tbl tablets (EX. 13) Batch(T/t)¹ K.F. AD MTAD SAMe SC  039 (20/0) 2.01 0.47 1.02 209.55 402.42039A (25/1) 2.15 0.55 1.32 210.39 401.37 039B (25/3) 1.92 0.73 1.43208.14 398.79 039C (25/6) 2.14 0.91 1.84 205.93 396.17

[0191] TABLE 76 Batch no. 040, 200 mg SAMe/tbl tablets (EX. 13) Batch(T/t)¹ K.F. AD MTAD SAMe SC  040 (20/0) 2.21 0.24 1.23 217.37 402.91040A (25/3) 1.88 0.33 1.37 216.73 401.10 040B (25/6) 2.03 0.57 1.49213.14 398.26 040C (25/12) 2.11 0.82 1.68 214.95 394.72

[0192] TABLE 77 Batch no. 041- 200 mg SAMe/tbl tablets (EX. 15) Batch(T/t)¹ K.F. AD MTAD SAMe MSM SC  041 (20/0) 1.88 0.51 1.71 205.15 503.32402.56 041A (25/3) 1.92 0.63 1.88 206.32 502.84 400.71 041B (25/6) 1.850.69 1.79 204.76 499.18 398.42 041C (25/12) 2.04 0.72 1.93 200.54 496.84399.70

[0193] TABLE 78 Batch 042- 200 mg SAMe/tbl tablets (EX. 15) Batch(T/t)¹K.F. AD MTAD SAMe MSM SC  042 (20/0) 1.72 0.45 1.64 223.54 502.64 404.35042A (25/3) 1.76 0.39 1.77 221.99 500.52 389.32 042B (25/6) 1.87 0.661.93 216.19 498.98 400.36 042C (25/12) 1.83 0.95 2.07 217.31 496.32393.40

[0194] TABLE 79 Batch no. 043, 200 mg SAMe/tbl tablets (EX. 15) Batch(T/t)¹ K.F. AD MTAD SAMe MSM SC  043 (20/0) 1.97 0.35 1.43 213.28 503.56402.73 043A (25/3) 1.81 0.47 1.49 209.39 500.04 401.99 043B (25/6) 1.650.50 1.61 210.34 496.22 397.43 043C (25/12) 1.79 0.87 1.95 207.68 495.74397.91

[0195] According to the stability data at 25° C. and 60% R.H. (shelflife), it can be noted that in all of the batches tested after 12months, both SAMe and the other active ingredients had undergone a verylow degradation.

1. A process for the preparation of tablets comprisingS-adenosylmethionine and/or one of the pharmaceutically and/or dietarilyacceptable derivatives thereof, comprising at a relative humidity, at20° C., lower or equal to 20%, the following steps: a) blending of theactive principle S-adenosylmethionine and/or a pharmaceutically anddietarily acceptable derivative thereof with 1.0-30.0% of calciumsulfate and/or phosphate, 1.0-10.0% of calcium and/or magnesiumcarbonate, 1.0-15.0% of glycerol behenate and/or palmitostearate and0.5-5.0% of silica, the amounts being expressed as weight percentages tothe weight of S-adenosylmethionine; b) compression of the mixtureresulting from step a); c) coating of the mixture resulting from step b)by 0.5-2.5% of Biogapress® vegetal and 0.5-2.5% of Labrafac®cc, at atemperature of 35′-45° C., after 10 to 30 minutes at 60° C.-65° C., thequantities being expressed as weight percentages to the total weight ofthe mixture resulting from step b).
 2. Process according to claim 1,comprising, after blending step a): a′) the pre-compression of themixture resulting from step a); and a″) the granulation of the mixtureresulting from step a′).
 3. Process according to claim 1, wherein thepharmaceutically and/or dietarily acceptable derivative ofS-adenosylmethionine is selected among the salts with sulfuric acidand/or paratoluensulfonic acid.
 4. Process according to claim 1,wherein, in step a), 1.0-30.0% by weight to the S-adenosylmethionineweight of anhydrous microcrystalline cellulose is added.
 5. Processaccording to claim 1, wherein the tablets are coated with agastroresistant film.
 6. Process according to claim 5, wherein thegastroresistant film comprises 1.0-5.0% of Eudragit® and/or Shellac®and/or at least a water-soluble salt of Shellac®, 1.0-3.0% of titaniumdioxide, 1.0-3.0% of talc, 0.1% -1.0% of triethylcitrate and/orglycerine, 0.004-0.04% of ferric oxide, the amounts being expressed asweight percentages to the total weight of the mixture resulting fromstep b).
 7. Process according to claim 5, wherein the gastroresistantfilm comprises 1.0-5.0% of Shellac® and/or at least a water-soluble saltof Shellac®, 1.0-3.0% of titanium dioxide, 1.0-3.0% of talc, 0.1-1.0% oftriethylcitrate, 0.004-0.04% of ferric oxide, the amounts beingexpressed as weight percentages to the total weight of the mixtureresulting from step b).
 8. Process according to claim 5, wherein thegastroresistant film comprises 1.0-5.0% of at least one water-solublesalt of Shellac®.
 9. Process according to claim 5, wherein thegastroresistant film comprises 1.0-5.0% of a 1:1 mixture of thepotassium and ammonium salts of Shellac®.
 10. Process according to claim1, wherein, in step a), at least another active ingredient is added. 11.Process according to claim 10, wherein said another active ingredient isselected among 100-150% of glucosamine sulfate, 80-120% of chondroitinsulfate, 100-150% of methylsulfonylmethane, 0.1-0.5% of vitamin B₆,0.04-0.2% of vitamin B₁₂, 0.03-0.15% of folic acid, the amounts beingexpressed as weight percentages to the weight of S-adenosylmethionine.12. Tablets comprising S-adenosylmethionine and/or one pharmaceuticallyand/or dietetically acceptable derivative thereof obtainable by theprocess according to claim 1.